RT Journal Article
SR Electronic
T1 Mitochondrial acetyl-CoA reversibly regulates locus-specific histone acetylation and gene expression
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201800228
DO 10.26508/lsa.201800228
VO 2
IS 1
A1 Lozoya, Oswaldo A
A1 Wang, Tianyuan
A1 Grenet, Dagoberto
A1 Wolfgang, Taylor C
A1 Sobhany, Mack
A1 Ganini da Silva, Douglas
A1 Riadi, Gonzalo
A1 Chandel, Navdeep
A1 Woychik, Richard P
A1 Santos, Janine H
YR 2019
UL http://www.life-science-alliance.org/content/2/1/e201800228.abstract
AB The impact of mitochondrial dysfunction in epigenetics is emerging, but our understanding of this relationship and its effect on gene expression remains incomplete. We previously showed that acute mitochondrial DNA (mtDNA) loss leads to histone hypoacetylation. It remains to be defined if these changes are maintained when mitochondrial dysfunction is chronic and if they alter gene expression. To fill these gaps of knowledge, we here studied a progressive and a chronic model of mtDNA depletion using biochemical, pharmacological, genomics, and genetic assays. We show that histones are primarily hypoacetylated in both models. We link these effects to decreased histone acetyltransferase activity unrelated to changes in ATP citrate lyase, acetyl coenzyme A synthetase 2, or pyruvate dehydrogenase activities, which can be reversibly modulated by altering the mitochondrial pool of acetyl-coenzyme A. Also, we determined that the accompanying changes in histone acetylation regulate locus-specific gene expression and physiological outcomes, including the production of prostaglandins. These results may be relevant to the pathophysiology of mtDNA depletion syndromes and to understanding the effects of environmental agents that lead to physical or functional mtDNA loss.